Patients with chronic kidney disease (CKD), including those on dialysis, have a substantially higher prevalence of hypothyroidism (HT) compared to their non-CKD counterparts. In the general population, HT is associated with increased cardiovascular (CV) morbidity and mortality, presumably due to atherosclerosis, platelet activation and thrombosis, and coronary heart disease (CHD) events. CKD patients have an exceedingly high CV mortality, with many of these fatalities related to CHD. However, little is known about the prognostic implications of HT on the CV health and survival of CKD patients. Dr. Connie Rhee is a nephrologist at the University of California Irvine (UCI) with a strong commitment to the fields of endo-nephrology and drug comparative effectiveness in CKD. Her long-term career goal is to become an independent patient-oriented investigator with a specific focus on thyroid functional disorders in kidney disease. The support of the K23 award will allow Dr. Rhee to achieve the following objectives: 1) investigate the impact of HT and its treatment on CHD risk and survival in CKD patients; 2) gain practical experience in the execution of patient-oriented research; 3) develop proficiency in navigating innovative multidisciplinary collaborations in nephrology, endocrinology, cardiovascular disease, and human subjects research; 4) and acquire expertise in advanced epidemiologic and biostatistical methods. In order to accomplish these objectives, Dr. Rhee will first examine the longitudinal impact of HT on mortality in a well-characterized prospective hemodialysis (HD) cohort in whom thyroid function will be rigorously defined using a combination of novel and traditional assays (Aim 1). She will then examine the association between HT and 3 specific CV surrogate endpoints (endothelial dysfunction, coronary artery calcification, and platelet activation) that represent major pathogenic mechanisms contributing to CHD risk in CKD (Aim 2). Lastly, she will examine the degree to which the association of HT with mortality is modified by underlying renal function in non-dialysis dependent CKD patients, and if these associations are ameliorated by thyroid hormone treatment using advanced analytic techniques (marginal structural modeling) that improve causal inference (Aim 3). Dr. Rhee will efficiently leverage resources from the NIDDK-sponsored Malnutrition, Diet, and Racial Disparities in CKD multicenter study and the unique strengths of the NIDDK-sponsored national Veterans Affairs (VA) database as she implements these Specific Aims. Findings from this proposed research will have the potential to uncover HT as a novel, modifiable risk factor for adverse CV outcomes in CKD; improve the diagnostic approach and management of this highly prevalent endocrine-renal disorder; and reduce the excess burden of CV death in this vulnerable population. Dr. Rhee will be closely guided by her primary mentor, Dr. Kamyar Kalantar-Zadeh, Professor and Chief of Nephrology at UCI whose vast experience in patient-oriented research will be complemented by Dr. Rhee's multidisciplinary co-mentor and collaborator team: 1) Dr. Gregory Brent, Professor, Chair of Medicine at the Greater Los Angeles VA, and renowned leader in thyroid hormone research; 2) Dr. Danh Nguyen, Professor and Director of the UCI Biostatistics, Epidemiology, and Research Design Unit with expertise in the longitudinal evaluation of CV risk factors in dialysis patients; 3) Dr. Steven Brunelli, Associate Epidemiologist at Brigham and Women's Hospital and Senior Director of DaVita Clinical Research with extensive experience in causal inference methods; 4) Dr. Csaba Kovesdy, Professor and Chief of Nephrology at the Memphis VA widely known for his research in the national veteran population; and 5) Dr. Matthew Budoff, Professor and Director of Cardiac Computed Tomography at Harbor UCLA with expertise in cardiovascular diagnostic imaging methods. Dr. Rhee will also draw upon the wealth of UCI's research environment, which includes the Harold Simmons Center for Kidney Disease Research and Epidemiology and the Division of Nephrology; the Institute of Clinical and Translational Science that is home to the Biostatistics, Epidemiology, and Research Design Unit; UCI's Departments of Epidemiology and Statistics; as well as the broader research enterprise of neighboring University of California campuses. Dr. Rhee's proposed K23 study, mentorship team, career development plan, and collaborative research environment will catalyze her scientific productivity and provide her with a strong foundation as a future independent investigator and leader in endo-nephrology.